The matrix metalloproteinases (MMP's) are a family of zinc containing endopeptidases which are capable of cleaving large biomolecules such as the collagens, proteoglycans and gelatins. Imbalance between active MMPs and endogenous inhibitors, leads to excessive tissue disruption. The three main groups of MMPs are the collagenases, the gelatinases, and the stromelysins. Collagenases include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8), and collagenase 3 (MMP-13). Gelatinases include 72 kDa gelatinase (gelatinase A; MMP-2) and 92 kDa gelatinase (gelatinase B; MMP-9). Stromelysins include stromelysin 1 (MMP-3), stromelysin 2 (MMP-10) and matrilysin (MMP-7). However there are MMPs which do not fit neatly into the above groups, for example metalloelastase (MMP-12), membrane-type MMP (MT-MMP or MMP-14) and stromelysin 3 (MMP-11).
Over-expression and activation of MMPs have been linked with a wide range of diseases such as cancer; rheumatoid arthritis; osteoarthritis; chronic inflammatory disorders, such as asthma, bronchitis and emphysema; cardiovascular disorders, such as atherosclerosis; corneal ulceration; dental diseases such as gingivitis and periodontal disease; neurological disorders, such as multiple sclerosis and restenosis. For example, MMP-12 is required for the development of cigarette smoke-induced emphysema in mice, Science, 277, 2002 (1997). Inhibition of MMPs is therefore a strategy for treatment of such disease states. However, there is evidence that non-selective inhibition of matrix metalloproteinase activity may affect normal physiological process leading to dose limiting side effects. Selective inhibition of MMP-12 and/or MMP-9 is thought to be a particularly relevant strategy for intervention in inflammatory conditions.
Some MMPs can hydrolyse the membrane-bound precursor of the pro-inflammatory cytokine tumour necrosis factor α: (TNF-α). This cleavage yields mature soluble TNF-α and some inhibitors of MMPs can block production of TNF-α both in vitro and in vivo. This pharmacological action is a probable contributor to the anti-inflammatory action of this class of compounds.
For a recent review of MMP inhibition as reflected in the patent literature, see Doherty et. al. Therapeutic Developments in Matrix Metalloproteinase Inhibition; Expert Opinions on Therapeutic Patents, 2002, 12, 665-707.
Very many of the MMP inhibitors of the prior art have a hydroxamic acid metal binding group (—CONHOH).